There are 2.5 million children living with HIV. The vast majority of these children acquired infection perinatally and are infected with HIV-1 clade C. Although antiretroviral therapy (ART) is effective, there are significant adherence and cost challenges associated with lifelong therapy in children. Drug sparing approaches such as therapeutic vaccines are needed for infected children. These strategies would try to achieve functional cure status in children resulting in an immunologic phenotype that closely resembles that of HIV elite controllers (ECs) who maintain undetectable viral loads in the absence of ART. CD4+ and CD8+ T cell responses are likely to play an important role in any therapeutic vaccination strategy. Although there has been a considerable expansion of our understanding of CD4+ T cell responses in adult EC and long-term non progressors (LTNPs) less is understood about these responses in children. In particular, very little is known about CD4+ T cell responses in children in sub-Saharan Africa who acquire infection while their immune system is immature and acquire co-infections such as CMV in childhood. CD4+ T cells are central to the adaptive immune response and are important for the development of virus specific CD8+ T cells that play an important role in host viral control. We will study HIV specific CD4+ T cell responses in a cohort of perinatally infected LTNP (pLTNPs), rapid progressors and slow progressors in southern Africa. We will determine if the specificity, breadth, magnitude, function and phenotype of CD4+ T cells determines viral control and disease progression. We will evaluate the magnitude, function and phenotype of virus specific CD8+ T cells and determine how they correlate with the CD4+ T cell responses. We will define how the thymus in these children maintains T cell homeostasis and how CD4+ and CD8+ T cell subtypes respond to regulatory cytokines such as IL-7 which are important for thymopoiesis, survival and peripheral expansion of nave and memory cells. We will also determine how immune reconstitution on ART affects virus specific T cell responses and T cell homeostasis in perinatally infected children. The data from this comprehensive study will lead to the identification of viral epitopes that are important in immune control some of which may be candidates for inclusion in therapeutic vaccines. The deficits in CD4+ and CD8+ T cell function and phenotype that will be identified will guide the development of strategies that may work to restore T cell function in these children. The study will broaden our understanding of the thymus and IL-7/IL-7R pathway in disease progression in a largely CMV positive population, and help us determine if IL-7 would be an appropriate adjunctive immunotherapy in this population. By longitudinally evaluating responses in perinatally infected children on ART, we will understand the deficits in immune restoration that occur despite ART and compare those responses to those identified in ART nave pLTNPs. This will help facilitate the development of therapeutic vaccines for children on ART that may enable them to develop an immune profile that resembles that in pLTNPs or ECs.